1. Field of the Invention
The present invention relates to a method and apparatus for clearing toxic substances from biological fluids, specifically blood, in which the fluid (the word "fluid" being used herein in the sense of liquid) flows along one side of at least one microporous diaphragm, whose pores are filled with a fluid which is not miscible with the biological fluid, while the other side of the diaphragm is contacted by a moving or flowing washing fluid.
In the case of acute liver failure, there is likely to be a complete loss of the detoxtying function of this organ for some time. This loss is especially important since in the case of liver failure, high levels of toxins are endogenically produced, causing inhibition of cerebral functions, resulting in a comatose condition; furthermore, the detoxitying function of the still-intact liver cells is thereby inhibited. In later stages, different aspects of the condition cause cumulative deterioration so that, in the end, death of the patient takes place.
Normally such toxins, which generally comprise phenols, mercaptans and fatty acids, are changed chemically, that is to say, by hydroxylation and conjugation in the liver itself into a water-soluble form, so that they may be excreted through the kidneys. This operation takes place enzymatically; for example materials such as phenols and the like are coupled/converted with the help of uridinediphosphoglucuronyl transferase (UDPGT) to glucuronides, which are soluble in water and may be excreted through the kidneys.
2. Description of the Prior Art
A great number of attempts have been made at using enzymatic conversion for clearing toxins from the human body of patients suffering from liver coma. For example, heterologous liver homogenates or slices of liver tissue, from which blood has been separated, suitably by dialysis, through a diaphragm, were used. Regrettably a quick loss in activity was noted within a short time and furthermore the exchange of toxins occurred very slowly if at all. Unfortunately, the use of a complete animal liver did not give rise to the desired effect, because of tissue incompatibility and it was not possible to supply nourishment thereto to the necessary degree.
For this reason, more and more suggestions were made to employ adsorbing materials, more specifically active charcoal, for the wider use of hemoperfusion (see the monograph by Brunner and Schmidt, Artificial Liver Support, Springer-Verlag, Berlin, 1981, starting at page 46). Such a process is, however, very unspecific since not only toxins, but a surprising number of other substances (which are important for supporting vital functions) which are taken from the blood. For example, the level of hormones in the blood goes down to nearly zero so that such treatment, on balance, gives rise to damaging effects.
Hemodialysis, in which water soluble products of metabolism are cleared from the body, is an unspecific way of separating substances. Thus toxins, which are normally hydrophobic, are not, as a rule, adequately cleared from the patient's body by this approach.
For this reason, experiments have been carried out with a liquid diaphragm enzyme reactor (see Brunner, et al, supra, page 219) for separating liver toxins by suing liquid diaphragm technology, which in the form noted earlier, was the result of the basic research work of Li; (see for example German patents 1,619,867, 2,222,067, 3,410,794, 3,779,907 etc.). Liquid diaphragm technology may be looked upon as extraction and stripping processes taking place at the same time, in which a dispersed emulsion is used in place of a simple solvent, as the separating phase. The term "liquid diaphragm" is generally used for the liquid components of a multi-emulsion, separating two liquids which, as a rule, are miscible with each other. For this reason blood or serum, containing the toxins to be cleared from the body therein, comprise one phase in which droplets are emulsified, the faces of such droplets forming the liquid diaphragm. These droplets for their part have a second phase separated within this diaphragm, the second phase comprising the reactant, as for example, the extracting liquid.
Such an emulsion is produced by the dropwise addition of the reactant to a liquid with a different polarity which contains surface-active substances. Thus an aqueous solution may be run dropwise into a long-chain hydrocarbon, as for example liquid paraffin, the latter preferably containing ionically surface-active materials, so that a stable emulsion is formed containing the aqueous solution in the form of droplets trapped within it. The liquid paraffin being responsible for forming the spherical outer face or layer, that is to say the liquid diaphragm. The stabilizing of such an emulsion is achieved by the effect of the surface-active substances, which are in fact bipolar reagents which, on the one hand, are solvated with the normally hydrophobic hydrocarbon chain by the liquid paraffin and, on the other hand, is solvated at their hydrophilic, normally ionic end group, by the water.
Such an emulsion is mixed with the liquid or fluid containing the material to be separated. If, for example, as noted in Brunner, et al. supra starting at page 219, phenol or naphthol is used in the form of an aqueous suspension and, if this solution is mixed with a liquid diaphragm emulsion having an enzyme solution trapped therein, it will be seem that the hydrophobic liquid diaphragm layer will be penetrated by the hydrophobic phenol, which will be contacted by the enzyme phase and thus changed by some form of conversion process into a hydrophilic reaction product, which can no longer diffuse back through the hydrophobic diaphragm. Hence, one of the most damaging toxins may be cleared from a system by extraction with a liquid diaphragm.
Although it might well seem that the extraction with liquid diaphragm technology is especially useful, there is the undesired effect such emulsions have to be again separated from the system which is to be cleaned or washed, this gives rise to a further working step. The separation of the emulsion is undertaken by separation of two phases, namely by centrifugation or by the addition of an emulsion breaking substance. In the first case, it is regrettably not possible to ensure that no traces of the emulsion remain in the system to be cleaned, furthermore, when the overall system is acted upon by high centrifugal forces, such forces especially in the case of biological fluids such as blood, destroy the blood corpuscles. Finally, the use of emulsion breaking substances is not possible with biological fluids, because these are generally toxic and, for this reason, may not be used for this purpose.
The natural separation of emulsions from an aqueous system has turned out to be impossible in the special case of biological fluids, because certain serious effects are produced, if such liquid diaphragm emulsions are put into direct contact with the blood.
Chem.-Ing.-Tech. 52 (1980), pages 399 to 410, discloses an account of supported liquid diaphragms made of polymeric microporous diaphragms, whose micropores are filled with organic liquids. These supported liquid diaphragms give the desired effect in the case of certain extraction operations, thus it should be possible to use this principle generally with diaphragms with the right properties. The correct constitution of such a supported liquid diaphragm for the processing of biological fluids has not previously been worked out, because such diaphragms have to be kept to rigid conditions. Such diaphragms have to be compatible with respect to the biological fluid, specifically blood and have to be filled with completely non-toxic liquids which, moreover will not become separated from the porous diaphragm. Furthermore, such diaphragms must have a very high level of separating efficiency to give the desired separation within the shortest possible treatment times.
However, this paper does not teach how these desired effects are to be produced and, in fact, is more directed to general observations on liquid diaphragm technology.